Hippocampal Receptors Research Articles

Neuroleptic profile of cipazoxapine (Savoxepine), a new tetracyclic dopamine antagonist: clinical validation of the hippocampus versus striatum ratio model of dopamine receptors in animals. A preliminary report.

Cipazoxapine is a new tetracyclic dopamine antagonist which we tested to validate an animal model for neuroleptics. This model was based on drug affinity to dopamine receptors in hippocampus versus striatum. For haloperidol the ratio was 0.67, for cipazoxapine 0.06. In this preliminary trial on eight schizophrenic patients we found that cipazoxapine in doses between 0.40 and 2 mg had an antipsychotic effect (measured by the BPRS) without extrapyramidal side-effects (measured by the Simpson-Angus-Scale). Our preliminary results thus support the animal findings.

Concomitant regulation of hippocampal calcium antagonist receptors and calcium uptake by Substance P

The interaction of various neuropeptides with calcium antagonist binding was investigated in rat hippocampus. Among the peptides examined Substance P selectively increased the binding of phenylalkylamine and dihydropyridine calcium antagonists; this action was receptor mediated. No effect was observed with Substance P in other brain areas and with neurotensin and met-enkephalin in all the areas examined. The modification in calcium antagonist binding is functionally paralleled by an area specific increase in voltage-dependent calcium uptake. These data suggest that in hippocampus Substance P may be an endogenous regulator of voltage sensitive calcium channels.

Hippocampal and renal type I receptors are differentially regulated.

Previously, we have shown that renal mineralocorticoid receptors and hippocampal "corticosterone-perferring" sites have identical intrinsic steroid specificity in vitro. Others have shown that the aldosterone binding species in kidney and hippocampus have identical trypsin fragmentation patterns on isoelectric focusing. To further explore possible areas of identity, we determined levels of type I receptors in hippocampus, renal outer medulla cortex, and renal inner medulla papilla from 22 min to 16 days after adrenalectomy. Available type I sites in kidney fractions increased postadrenalectomy to plateau levels in 22 (inner medulla papilla) or 90 min (outer medulla cortex). In contrast, available hippocampal receptors attained maximal levels 24-48 h postadrenalectomy. Animals, 24-h adrenalectomized, showed no differences in steroid uptake or washout between kidney and hippocampus, determined by in vitro tracer binding 22 or 90 min after intravenous aldosterone or corticosterone. We interpret the marked difference in receptor levels between kidney and hippocampus postadrenalectomy as evidence for tissue-specific differences in the control of receptor levels by endogenous steroids.

Selectivity of pirenzepine in the central nervous system. II. Differential effects of pirenzepine and scopolamine on performance of a representational memory task

The behavioral effects of the two muscarinic antagonists scopolamine and pirenzepine were examined using a representational memory task for rats in a T-maze. Rats were pretrained to a criterion of 100% correct responses for daily sessions of 10 paired-run trials. The training procedures eliminated all neophobic or wary responses, and response times were invariably short (<3 s). Following the initial training sessions, guide cannulae were surgically implanted bilaterally over the hippocampus of each animal. Following recovery from surgery, animals were injected with saline (0.5 μl to each hippocampus), scopolamine hydrobromide (0.5 μl of a 60 mg/ml solution (30 μg) to each side), or pirenzepine (0.5 μl of a 69.1 mg/ml solution (34.6 μg) to each side) according to a fixed schedule. Saline injections aimed between the blades of the dorsal dentate gyrus failed to produce any change in the performance of the memory task. Initial doses of scopolamine, applied to the same area, produced a decrease in the percentage of correct responses as did the initial dose of pirenzepine. In contrast to pirenzepine, scopolamine also produced increases in response times even to the point of defaulted trials (response times >90 s) in some animals following drug injections. Saline injections failed to produce significant impairments on the days following scopolamine injections, although animals receiving pirenzepine injections were still impaired on the two days immediately following the initial pirenzepine injection. Subsequent doses of pirenzepine were ineffective in producing an impairment of performance while scopolamine injections were less effective than the initial dose. The results show that pirenzepine, which was previously found to be more selective than scopolamine for hippocampal receptors, is also more selective in producing representational memory deficits, suggesting an involvement of M 1 muscarinic receptors in representational memory.

The status of hippocampal cholinergic receptors in human cognitive disorders

The status of hippocampal cholinergic receptors in human cognitive disorders

Density and distribution of NMDA receptors in the human hippocampus in Alzheimer's disease

We examined the distribution and density of N-methyl- d-aspartate (NMDA) displaceable l-[ 3H] glutamate binding sites in human hippocampal samples obtained postmortem from Alzheimer's disease (AD) patients and from age-matched controls. Binding to NMDA receptors was stable for at least 72 h postmortem, and the pharmacological profile corresponded to that described using electrophysiology. NMDA receptors were concentrated in the terminal fields of major hippocampal pathways including the perforant path, Schaffer collaterals and the hippocampal output to the subiculum, all of which are proposed to use an excitatory amino acid transmitter. Little if any change in hippocampal receptor density was observed in AD patients compared to age-matched controls except in one case where major hippocampal cell loss occurred. The distribution of NMDA receptors did, however, correspond to the predilection for neuritic plaques and neurofibrillary tangles in hippocampal subfields.

Vasopressin-neurophysin and bipolar depression

Vasopressin-neurophysin is a part of the precursor molecule for the active nonapeptide vasopressin (antidiuretic hormone, AVP). In humans, this neurophysin has a marked anodal electrophoretic migration and is therefore named neurophysin-I (hNpI) (Legros and Louis 1973) (see review of the precursor in lvell et al. 1983). AVP and hNpI are released simultaneously by exocytosis of neurosecretory granules in the peripheral circulation and in the cerebrospinal fluid (CSF): modifications of hNrI concentrations therefore reflect the ~uctuations of AVP release in different physiological and pathological conditions. Moreover, as hNpI is more stable than AVP, its blood and CSF levels might better reflect long-term vasopressinergic function than isolated AVP assays (see discussion in Legros 197.5). Since the pioneer work of de Wied (1965). there has arisen a growing evidence that vasopressin has a central activating action (mood, memory, selective attention) in animals and humans (de Wied 1977; Legros et al. 1978; Kovaks et al. 1979; Weingartner et al. 1981: Legros and Lancranjan 1984). The recent discovery of hippocampal receptors for AVP and the close correlation between the in vitro binding affinity and the in vivo behavioral power of different vasopressin analogs or derivatives (Audigier and Barberis 1985) reinforce the psychophysiological meaning of this peptide action on the brain. Based on this activity. Gold et al. (1978) postulated that vasopressin release can be aitered in some psychopathological conditions, and more p~icul~ly, in depression and mania. However, basal plasma levels did not differ in the different groups of patients, whereas sophisticated challenge tests (hypertonic saline infusion) revealed decreased release during the depressive phase and increased response during the manic phase (Gold et al. 1983a). We have also previously described an increase of CSF neurophysins in bipolar as compared to unipolar depressed patients (Legros et al. 1983; Linkowski et al. 1984). We therefore decided to investigate basal and apomorphine-stimulated neurophysin serum levels in different psychopathological conditions. In the course of that study, we recently had an opportunity to test one bipolar patient who had never been treated with lithium, during consecutive depressive and manic episodes while remaining completely unmedicated.

Repeated imipramine treatment increases the responsivity of the rat hippocampus to dopamine. Anin vitro study

The sensitivity of hippocampal neurons to dopamine was studied in hippocampal slices obtained from rats treated acutely (10 mg/kg) or repeatedly (10 mg/kg, 14 days, twice a day) with imipramine. In non-treated rats dopamine induced a slight excitation or depression of the firing rate of CA 1 pyramidal neurons in slice preparations. Hippocampal slices prepared from the imipramine-treated rats displayed greater changes in the firing rate after dopamine application. Repeated imipramine administration also increased the number of slices sensitive to dopamine. it is concluded that repeated imipramine administration induces supersensitivity of hippocampal dopamine receptors.

In Vivo and in Vitro Characterization of Dopamine Receptors in Hippocampus and their Pharmacological Relevance

In Vivo and in Vitro Characterization of Dopamine Receptors in Hippocampus and their Pharmacological Relevance

Arginine-vasopressin stimulates inositol phospholipid metabolism in rat hippocampus.

The hippocampal vasopressin receptors have been characterised by measuring the stimulated accumulation of inositol monophosphate in the presence of 10 mM LiCl after hippocampal slices were prelabelled with [3H]inositol. Arginine-vasopressin caused a dose-dependent increase in inositol monophosphate accumulation (ED50 = 7.1 nM). The response was unchanged in the absence of Ca2+ and significantly reduced in the presence of a V1-receptor antagonist. Equimolar oxytocin was ineffective as a stimulus. This suggests that the hippocampal receptors are of the V1 type.

Selective control by corticosterone of serotonin1 receptor capacity in raphe-hippocampal system.

The effect of short-term bilateral adrenalectomy (ADX) and corticosterone or aldosterone replacement was investigated on serotonin1 (5-HT1) receptor density in rat brain regions. One hour after ADX the 5-HT1 receptor density was increased in subiculum, molecular layer of the dentate gyrus, substantia nigra, and dorsal raphe nucleus as shown by in vitro autoradiography and computerized densitometric analyses of the film images. In subiculum, dentate gyrus, and dorsal raphe nucleus the 5-HT1 receptor density was restored (decreased) towards the level observed in sham-operated rats after administration of a low dose of corticosterone (CORT) at the time of ADX. CORT replacement decreased the 5-HT1 receptor number also in hippocampal pyramidal cell layer CA1, presubiculum, and other dentate gyrus subregions. The 5-HT1 receptor density was not affected by ADX or CORT replacement therapy in cerebral cortex, central grey, CA3, ventral hippocampus, and median raphe nucleus. Aldosterone administered under the same experimental conditions did not change the 5-HT1 receptor number in any of the hippocampus or raphe regions. The dose of CORT (30 micrograms/100 g body weight, s.c.) gave physiological plasma levels and maintained almost complete occupation of CORT receptors (mineralo-corticoid-like receptors) in hippocampus which was also the case in the sham-operated control animals. CORT replacement did not maintain occupancy of glucocorticoid receptors in hippocampus. When the binding of the selective glucocorticoid agonist, 3H-RU 28362, was taken as 100% at 1 h after ADX, CORT replacement and sham ADX left 75 and 50% of these sites available respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain.

The effects of lithium treatment on serotonin (5-HT) receptors in rat frontal cortex and hippocampus were investigated. Long-term lithium treatment strongly blocked 5-hydroxytryptophan-induced head twitches, while acute lithium administration by itself induced head twitches in rats, and ketanserin blocked this acute lithium action. Long-term administration of lithium decreased the number of not only 5-HT2 receptors in the frontal cortex but also 5-HT1 and 5-HT2 receptors in the hippocampus in rats. Decreases in 3H-5-HT binding to hippocampal 5-HT1 receptors and 3H-spiperone binding to frontal cortical 5-HT2 receptors, caused by chronic lithium treatment, were abolished by co-administration of p-chlorophenylalanine, and were enhanced by co-administration with methiothepin. The turnover of 5-HT in either frontal cortex or hippocampus was facilitated by lithium, and co-administered methiothepin enhanced this facilitation. These results suggest that long-term lithium treatment causes the down-regulation of postsynaptic 5-HT1 and 5-HT2 receptors, in part probably through its action on presynaptic nerve terminals.

The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation

In order to characterize the development of the glucocorticoid receptor system in the brain, we examined [ 3H]dexamethasone binding in rat pups at various ages. Using an in vitro, cytosol, receptor assay we found evidence for low levels of glucocorticoid receptors perinatally with a subsequent increase in receptor concentrations that began by about the end of the first week of life. We have also shown that receptors during this period have a ligand specificity similar to that of receptors in adult animals. The postnatal increase in receptor levels parallels an increase in circulating corticosterone titers. Thus, receptor and hormone levels increase coincidentally. In adult animals, however, increasing levels of corticosterone are associated with a decrease in receptor levels and vice versa, such that corticosterone is thought to regulate its own receptor (i.e. autoregulation). This suggested an absence of autoregulation during development. We then determined hippocampal receptor concentrations of rats treated for 5 days with corticosterone, or adrenalectomized (ADX) 5 days prior to assay, examining whether up- or down-regulation occurs throughout development. In adults corticosterone treatment decreased (−45%) and long-term adrenalectomy increased (211%) glucocorticoid receptor concentrations. In contrast, at the youngest age tested (Day 10), the effects of manipulations of corticosterone titers on receptor concentrations were negligible. The potential for autoregulation emerged gradually throughout development. Thus, it appears that corticosterone regulation of its own receptors emerges only by about the time of puberty, and that this permits an increase in receptor levels to occur despite the concurrently increasing levels of circulating corticosterone.

Do vasopressin-related peptides induce hippocampal corticosterone receptors? Implications for aging

The aged rat shows a decline in hippocampal corticosterone receptors and dysfunction in learning and adrenocortical physiology previously linked to glucocorticoid effects upon the hippocampus. The Brattleboro rat, congenitally lacking vasopressin, also has a low number of hippocampal glucocorticoid receptors, as well as learning and endocrine impairments similar to those seen in the aged. Centrally acting vasopressin analogues correct the receptor loss in the hippocampus in the Brattleboro rat but do not influence the hippocampal receptor deficit in the aged rat. Quantitative and high resolution autoradiographic procedures were utilized to characterize the glucocorticoid receptor deficit in the aged and Brattleboro rats. Quantitative autoradiography showed that in both aged and Brattleboro subjects, losses in receptors were most extreme in the pyramidal layer of the CA3a region. High resolution autoradiography revealed striking differences in the cellular basis of the receptor losses. Brattleboro rats had decreased binding of [3H]corticosterone per neuron, whereas aged subjects, in addition, had significant losses in the number of corticosterone-concentrating neurons. Taken together, our findings indicate that the glucocorticoid receptor deficit in the Brattleboro rat probably represents a vasopressin-influenced defect in the synthesis or degradation of the receptor, whereas in the aged rat the deficit originates from loss of both receptor per neuron and the steroid-concentrating neurons themselves, and thus is most likely a permanent and pharmacologically insensitive deficit.

Classification and properties of acidic amino acid receptors in hippocampus. I. Electrophysiological studies of an apparent desensitization and interactions with drugs which block transmission

Classification and properties of acidic amino acid receptors in hippocampus. I. Electrophysiological studies of an apparent desensitization and interactions with drugs which block transmission

Selective localization of different types of opiate receptors in hippocampus as revealed by in vitro autoradiography

The visualization of opiate binding sites within the hippocampus of the rat has been achieved by means of an in vitro autoradiography. In line with the concept of multiple opiate receptors, different opioid agonists revealed a particular distribution pattern. Whereas the selective δ-receptor agonist [ 3H] d-Ala 2, d-Leu 5-enkephalin specifically labelled binding sites in the CA 2 area, [ 3H]etorphine grains displayed a uniform dense distribution throughout the pyramidal cell layers from CA 1 to CA 4.

In vivo [ 3H]spiperone binding to the rat hippocampal formation: Involvement of dopamine receptors

The existence of DA receptors in the rat hippocampus was demonstrated with an in vivo [ 3H]spiperone radio-receptor assay. Kinetic studies revealed that maximum binding of [ 3H]spiperone in hippocampus was much smaller than in striatum and frontal cortex but much higher than in cerebellum. In inhibition studies of [ 3H]spiperone binding, all neuroleptics tested were active in hippocampus as well as in striatum. In contrast, 5HT antagonists were definetely less potent in these two brain regions than in frontal cortex. Finally, even when 5HT receptors were blocked, dipropyl-ATN and haloperidol remained fully effective in hippocampus, striatum, but also in frontal cortex although to a lesser degree. From these results it was concluded that [ 3H]spiperone binds mainly to DA receptors in hippocampus as well as in striamtum, whereas both 5HT and DA receptors are present in frontal cortex.

Development of muscarinic cholinergic receptors in inbred strains of mice: Identification of receptor heterogeneity and relation to audiogenic seizure susceptibility

The concentrations and biochemical properties of muscarinic acetylcholine receptors in the brains of two highly inbred strains of mice, DBA/2J and C57BL/6J, have been studied using [ 3H]quinuclidinyl benzilate (QNB), a potent and specific receptor antagonist. As is the case with rat brain, murine muscarinic receptors exist in at least two forms, which differ in their affinities for receptor agonists but which have the same high affinity for receptor antagonists. Carbamylcholine binding to mouse neural membranes can be resolved into two components with K Ds of 5.2 × 10 −7 and 7.9 × 10 −5 M. There is a regional heterogeneity of brain receptors with respect to their distribution between these high and low agonist affinity forms. Brain stem and hypothalamus receptors display binding properties that would be expected if over 60% of their receptors were in the high affinity state, while only 30–40% of cortex, striatum and thalamus receptors appear to be in the high affinity form. Hippocampal receptors display the least amount of high agonist affinity character. Saturation curves and Scatchard plots of QNB binding at 2, 14, 21 and 42 days postnatal age in both strains indicate no differences or changes in the affinity or nature of the binding with age. Significant increases in QNB binding per mg membrane protein were observed between 14 and 42 days in the cortex, hippocampus, striatum, thalamus and hypothalamus, but not in the midbrain-pons-medulla region. In the hippocampus the DBA mice had significantly more QNB bindin. In the hypothalamus decreases with age in total binding were noted in DBA, while slight increases were noted in C57. Compared to C57, hippocampal receptors in DBA displayed lower agonist affinity at 14 and 21 days, a trait which was not apparent when DBA had outgrown their audiogenic seizure sensitivity at 42 days. The differences in receptor density and agonist state distribution between the two strains may be related to audiogenic seizure sensitivity.

Characteristics of dexamethasone binding to hippocampal cytosol receptors.

This study was designed to clarify an in vitro system which could be used to study the time course, kinetics, and specificity of [3H]-dexamethasone (DM) binding in hippocampal cytosol. Maximal binding, as measured by chromatography through Sephadex LH-20 mini-columns, was attained by 6 h and maintained to 24 h when the incubation medium contained 20 mM Tris, 20% glycerol, 50 mM KC1, 20 mM monothioglycerol, pH 7.8. Cytosol from adrenalectomized pigs exhibited a 50% greater capacity to specifically bind DM than that from unadrenalectomized pigs. Non-specifically bound DM averaged 18 ± 5% of total [3H]-dm bound. The calculated Kd was 1.07 × 10−10 M and the maximum number of binding sites was 3.0 × 10−14 moles/mg protein. Thirty-three hours were required for the dissociation of half of the specifically bound [3H]-DM. Instability of the complex increased as incubation temperature was raised. Binding activity was diminished by competition with glucocorticoid or anti-glucocorticoid hormones and by incubation with proteolytic enzymes. It was demonstrated that DM binding in porcine serum is limited and that possible contamination of this system with CBG had negligible effects. Thus a glucocorticoid receptor exists in porcine hippocampal cytosol and can be characterized by its high affinity and specificity as different from CBG.

Putative acetylcholine receptors in hippocampus and corpus striatum of rat and mouse

Putative acetylcholine receptors in hippocampus and corpus striatum of rat and mouse